VEGF Signaling Pathway Inhibitors Research Articles

Kidney Disease Patient Representation in Trials of Combination Therapy With VEGF-Signaling Pathway Inhibitors and Immune Checkpoint Inhibitors: A Systematic Review

Kidney Disease Patient Representation in Trials of Combination Therapy With VEGF-Signaling Pathway Inhibitors and Immune Checkpoint Inhibitors: A Systematic Review

Impact of hypertension on clinical outcome in patients treated with vascular endothelial growth factor inhibitors

Abstract Background Vascular endothelial growth factor (VEGF) family is overexpressed in the tumor microenvironment and induces tumor angiogenesis.1 VEGF signaling pathway (VSP) inhibitors are essential therapeutic drugs for solid cancer patients.2 However, VSP inhibitors often provoke drug-specific anti-angiogenesis in normal tissues, which was referred to as on-target toxicity.2 Hypertension (HTN) is one of the most frequent adverse events caused by VSP inhibitors. A previous report demonstrated that VSP inhibitor-induced hypertension is a favorable prognostic factor, contrarily.3However, multiple VSP inhibitors are administered in various cancer types, and then the relation between VSP inhibitor-associated hypertension and clinical outcome is still controversial. Purpose The aim of this study is to elucidate the impacts of HTN and the timing of onset on clinical outcome during cancer therapy with VSP inhibitors. Method We reviewed 2,348 patients who were treated with VSP inhibitors from the LIFE Study database, consisting of 14 municipality-level information from claims data between 2016 and 2020. According to the timing of HTN onset mode, the patients were stratified into 3 groups; (1) new-onset HTN group (n=334): de novo development after VSP inhibitor administration, (2) pre-existing HTN group (n=1,363): existing HTN at baseline, including aggravation after VSP inhibitor initiation, and (3) no HTN group (n=651) (Figure 1). The time to treatment failure (TTF) was applied as a surrogate clinical indicator of overall survival. Event-free survival analysis with the log-rank test was conducted for time to first treatment failure amongst the 3 groups. In addition, Cox proportional hazard models adjusted with clinical characteristics were performed to investigate independent factors for TTF. Results In the event-free survival analysis, both the new-onset HTN and the pre-existing HTN were associated with prolongation of TTF, compared to the non-HTN (p<0.001 and p<0.001, respectively, by Bonferroni correction) (Figure 2). The New-onset HTN was significantly associated with longer TTF than pre-existing HTN (p<0.001). In Cox proportional hazard model adjusted with age, sex, past medical history, primary cancer lesion, and type of VSP inhibitors, the new-onset HTN and the pre-existing HTN were independent favorable factors, compared to the non-HTN [new-onset HTN: Hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.54 - 0.71, p<0.001; and pre-existing HTN: HR 0.85, 95% CI 0.77 - 0.94, p<0.005]. Moreover, the New-onset HTN was also a significant factor for longer TTF, compared to the pre-existing HTN [HR 0.72, 95% CI 0.64 - 0.82, p<0.001]. Conclusion In patients treated with VSP inhibitors, both new-onset and pre-existing HTN are independent factors for a favorable clinical outcome, especially new-onset HTN after VSP inhibitors administration. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (KAKENHI) Figure 1. Patient screening and enrollmentFigure 2. HTN & TTF

Influence of miR-199a on rats with non-small cell lung cancer via regulating the HIF-1α/VEGF signaling pathway.

Micro-ribonucleic acids (miRNAs) are involved in the occurrence of various cancers, and the hypoxia-inducible factor 1-α (HIF-1α) is the main regulator of cell proliferation induced by hypoxia. The relationships of miR-199a and HIF-1α expressions with non-small cell lung cancer (NSCLC) remain unclear, so they were explored in this work. On the basis of establishing the rat model of NSCLC, the messenger RNA (mRNA) expressions of miR-199a, HIF-1α and the vascular endothelial growth factor (VEGF) were analyzed in NSCLC rats, and the correlations of miR-199a with the mRNAs of HIF-1α and VEGF and cancer staging were investigated. To further study the role of miR-199a in NSCLC cell proliferation via the HIF-1α/VEGF signaling pathway, NSCLC cells were treated with the signaling pathway inhibitor and transfected with miR-199a mimics, respectively. Also, the roles of the inhibitor PX-478 and miR-199a mimics in the expressions of miR-199a, HIF-1α, and VEGF proteins, as well as their influences on cell proliferation ability were detected. In NSCLC rats, the expression of miR-199a was substantially decreased (p<0.01), but the expressions of HIF-1α and VEGF were notably raised (p<0.01). MiR-199a was negatively correlated with the expression of VEGF. As cancer developed, the expression of miR-199a was gradually lowered, but the expressions of HIF-1α and VEGF were gradually increased. Both HIF-1α/VEGF signaling pathway inhibitor PX-478 and miR-199a mimics significantly reduced the expressions of HIF-1α and VEGF proteins (p<0.01) and suppressed the cell proliferation activity. MiR-199a prevents the proliferation of NSCLC cells via the targeted down-regulation of the HIF-1α/VEGF signaling pathway.

Acute blood pressure elevation associated with biological therapies for cancer: a focus on VEGF signaling pathway inhibitors

ABSTRACTIntroduction: Treatment with biological agents interfering with mechanisms of angiogenesis, such as vascular endothelial growth factor (VEGF) signaling pathway (VSP) inhibitors, was associated with an enhanced risk of acute and severe blood pressure (BP) increase and development of hypertensive emergencies.Areas covered: The present article will review the scientific literature reporting hypertensive emergencies as a complication of biological treatment with VSP inhibitors. Hypertensive emergency is a life-threatening condition characterized by very high BP values (>180/110 mmHg) associated with acute organ damage. The exact mechanism of action is still incompletely clarified. Endothelial dysfunction following reduced bioavailability of nitric oxide has been hypothesized to play an important role in promoting hypertension and the occurrence of acute organ damage.Expert opinion: Prevention, prompt recognition and treatment of hypertensive emergencies associated with treatment with VSP-inhibitors are essential to reduce the risk of adverse events. Not infrequently, the occurrence of hypertensive emergency led to VSP treatment discontinuation, with potential negative consequences on patient overall survival. The present review aims at providing detailed knowledge for the clinician regarding this specific issue, which could be of high impact in usual clinical practice, given the increasing burden of indications to treatment with biological agents targeted to the VEGF pathway.

Tyrosine Kinase Inhibitor-Induced Hypertension.

The purpose of this paper is to identify commonly used tyrosine kinase inhibitors (TKIs) that are associated with hypertension, primarily, vascular endothelial growth factor (VEGF) signaling pathway (VSP) inhibitors. We review the incidence, mechanism, and strategies for management of TKI-induced HTN. We hope to provide clinicians with guidance on how to manage similar clinical scenarios. Many of the newer VSP inhibitors are reviewed here, including cediranib, axitinib, pazopanib, and ponatinib. Trials utilizing prophylactic treatment with angiotensin system inhibitors (ASIs) are discussed as well as recent data showing an improvement in overall survival and progression-free survival in patients on ASIs and TKI-induced hypertension. The incidence of TKI-induced HTN among the VEGF inhibitors ranges from 5 to 80% and is dose dependent. Newer generation small-molecule TKIs has a lower incidence. The mechanism of action involves VSP inhibition, leading to decreased nitric oxide and increased endothelin production, which causes vasoconstriction, capillary rarefaction, and hypertension. ASIs and calcium channel blockers are first-line therapy for treatment and are associated with improved overall survival. Nitrates and beta-blockers are associated with in vitro cancer regression; however, there is a paucity of trials regarding their use as an anti-hypertensive agent in the TKI-induced HTN patient population.

Mechanisms of VEGF (Vascular Endothelial Growth Factor) Inhibitor-Associated Hypertension and Vascular Disease.

The VEGF (vascular endothelial growth factor) pathway has emerged as an important target for cancer therapy, with VEGF signaling pathway (VSP) inhibitors having been approved for several different malignancies. Less anticipated has been the multitude of cardiovascular and renal effects of these therapies. Hypertension occurs in at least a quarter of patients starting VSP inhibitors, with virtually every patient having an absolute increase in blood pressure. Patients can also develop proteinuria, renal dysfunction, vascular events, or cardiomyopathy. Although these toxicities have been generally manageable, they have introduced cardiovascular and renal considerations for patient care. On the other hand, these sequelae have provided a growing appreciation for the critical role of VEGF in vascular and renal homeostasis in human biology. Although several recent articles have addressed practical considerations with respect to patient care with this class of drugs,1–4 this review will explore mechanisms associated with the vascular toxicities arising from VEGF signaling inhibition in cancer treatment. The human VEGF family consists of 5 related glycoproteins: VEGFA, VEGFB, VEGFC, VEGFD, and PIGF (placental growth factor). These are secreted to form homodimers, which interact with a family of 3 receptor tyrosine kinases: VEGFR1 (VEGF receptor 1), VEGFR2, and VEGFR3 (Figure 1). VEGFA and VEGFB bind to VEGFR1, VEGFA binds to VEGFR2, and VEGFC and VEGFD bind to both VEGFR2 and VEGFR3.1,5 PIGF primarily interacts with VEGFR1. The VEGFRs are found on a wide variety of cell types. VEGFR1, also called Flt-1 (fms-like tyrosine kinase 1), is found on vascular endothelial cells, hematopoietic stem cells, monocytes, and macrophages. VEGFR2, also called KDR (kinase insert domain) or Flk-1 (fetal liver kinase 1), is expressed on vascular and lymphatic endothelial cells; VEGFR3 (also called Flt-4) is restricted to lymphatic endothelial cells.5 On ligand binding, VEGFRs transduce intracellular signals through …

Use of Antihypertensive Drugs in Neoplastic Patients.

The introduction of Vascular Endothelial Growth Factor (VEGF) signaling pathway inhibitor treatment has highlighted the role of the baseline activity of the VEFG system for blood pressure regulation. VEGF signaling pathway is associated with hypertension and proteinuria. Activation of the endothelin system, endothelial dysfunction and capillary rarefaction are among the underlying mechanisms possibly explaining the rise in blood pressure and, to some extent, also the renal injury. The hypertension induced by VEGF signaling pathway inhibition is, usually, responsive to treatment. Recommendations about the management of cardiovascular toxicity in patients receiving VEGF signaling pathway inhibitors include a formal cardiovascular risk assessment before initiation of VEGF signaling pathway inhibitor treatment, active monitoring of blood pressure and cardiac toxicity throughout treatment, with more frequent monitoring during the first cycles of therapy, given that marked and unpredictable blood pressure rises can occur early after treatment with a VEGF signaling pathway inhibitor, and aggressive management of blood pressure elevations and early symptoms and signs of cardiac toxicity to prevent clinically limiting complications. In patients with preexisting hypertension, the blood pressure target for initiating VEGF signaling pathway inhibitor treatment should be <140/90mmHg. Blockers of the renin-angiotensin system and calcium channel antagonists are among the drugs to be preferably used in these clinical conditions.

Mechanisms of Hypertension and Renal Injury During Vascular Endothelial Growth Factor Signaling Inhibition.

The recognition that angiogenesis is critical for tumor growth has stimulated the development of several agents that interfere with the process of angiogenesis. Of these agents, vascular endothelial growth factor (VEGF) signaling pathway (VSP) inhibitors have gained a prominent role in the treatment of a large variety of cancers. Along with their clinical introduction, treatment with VSP inhibitors appeared to be associated with the development of cardiovascular side effects, particularly hypertension, renal injury, cardiac dysfunction, thrombosis, and hemorrhage. When severe, these side effects are reason to discontinue VSP inhibitor treatment, obviously with repercussions for survival. In this review, we focus on mechanisms underlying the rise in blood pressure (BP) and kidney injury induced by VSP inhibitor treatment. Insight into the mechanisms of these side effects is not only of scientific interest, but may also provide a basis for their prevention with rational treatment. Because for a proportion of clinicians interested in hypertension the VEGF system is not common knowledge, we will start with a short description of this system and ways of its inhibition by pharmacological agents. The mammalian VEGF family includes the glycoproteins VEGF-A,VEGF-B, VEGF-C, VEGF-D, VEGF-E, and the placental growth factor, with VEGF-A, commonly referred to as VEGF, as the most prominent factor. The VEGFs are mainly present as homodimeric polypeptides. Alternative splicing and proteolytic processing increase the complexity of the VEGF system. For instance, alternative splicing of the gene encoding for VEGF-A gives rise to VEGF isoforms exerting antiangiogenic activity.1 VEGF is produced by most parenchymal cells, acting in a paracrine fashion on adjacent endothelial cells (ECs). The induction of VEGF is crucial for the initiation of angiogenesis, with hypoxia-inducible factor 1α and 2α and platelet-derived growth factor B as important positive regulators of its production.2 Genetic deletion experiments in mice have shown that the …

Tube formation in the first trimester placental trophoblast cells: Differential effects of angiogenic growth factors and fatty acids.

The study aims to investigate whether cytosolic fatty acid-binding protein-4 (FABP4) is involved in angiogenic growth factors- and fatty acid-induced tube formation in first trimester placental trophoblast cells, HTR8/SVneo. We determined the tube formation both at basal as well as stimulated levels in the absence and presence of inhibitors of FABP4 and VEGF signaling pathways. Basal level of tube formation was maximally reduced in the presence of 50 µM of FABP4 inhibitor compared with those by VEGF signaling pathway inhibitors (rapamycin, L-NAME, and p38 MAP kinase inhibitor). Whereas docosahexaenoic acid, 22:6n-3 (DHA)-, and VEGF-induced tube formation was maximally inhibited by p38 MAP kinase inhibitor (63.7 and 34.5%, respectively), however, leptin-induced tube formation was inhibited maximally by FABP4 inhibitor (50.7%). ANGPTL4 and oleic acid (OA)-induced tube formation was not blocked by any of these inhibitors. The FABP4 inhibitor inhibited cell growth stimulated by DHA, leptin, VEGF, and OA (P < 0.05) but was not affected by ANGPTL4. VEGF, leptin, and OA also increased FABP4 protein level in these cells, though the uptake of fatty acids by these cells was not affected by the presence of FABP4 inhibitor. Our data demonstrate that FABP4 may be involved in part in the basal level, and stimulated tube formation by VEGF, DHA, and leptin, whereas it has little or no effect in ANGPTL4- and OA-induced tube formation in these cells. Thus, FABP4 may play a differential role in fatty acids and angiogenic growth factors-mediated tube formation in the first trimester trophoblast cells in vitro.

Hypertension in cancer patients treated with anti-angiogenic based regimens.

New anti-cancer drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway are highly effective in the treatment of solid tumors, however concerns remain regarding their cardiovascular safety. The most common side effect of VEGF signaling pathway (VSP) inhibition is the development of systemic hypertension. We review the incidence, possible mechanisms, significance and management of hypertension in patients treated with VSP inhibitors.

Recognizing and managing left ventricular dysfunction associated with therapeutic inhibition of the vascular endothelial growth factor signaling pathway.

Therapeutic inhibition of the vascular endothelial growth factor (VEGF) signaling pathway (VSP) is increasingly employed in the contemporary treatment of many cancer types. VSP inhibitors include the anti-VEGF monoclonal antibody (bevacizumab), soluble VEGF receptors (VEGF Trap), and small molecule tyrosine kinase inhibitors (TKIs) targeting the intracellular kinase domain of VEGF receptors. These agents are associated with cardiovascular toxicities such as hypertension, thrombosis, myocardial ischemia, and left ventricular (LV) dysfunction. Data on VSP inhibitor-associated LV dysfunction are largely limited to retrospective studies. Prospective studies are needed to establish the clinical significance of VSP inhibitor-associated LV dysfunction in the general population. Pre-clinical models of VSP inhibitor-associated LV dysfunction have identified mechanisms of cardiotoxicity and may improve our understanding of the pathophysiology underlying other cardiomyopathies. This review provides an overview of LV dysfunction that can occur in patients treated with VSP inhibitors. Potential strategies for clinical detection and management of this cardiotoxicity are explored, while acknowledging that currently available data specific to VSP-inhibitor LV dysfunction are limited. Avenues for future research are suggested.

Effect of baseline characteristics, including antihypertensive therapy, on survival and hypertension during treatment with vascular endothelial growth factor (VEGF) signaling pathway inhibitors (VSP-Is).

9639 Background: Oral VSP-Is are associated with a significant risk of hypertension (HTN), yet little is known regarding clinical predictors. We describe the association between baseline clinical characteristics, including antihypertensive (antiHTN) therapy, and increased blood pressure (BP) and survival in patients prescribed VSP-Is. Methods: Clinical data was obtained from1120 adults prescribed VSP-Is, identified from electronic medical records (Partners HealthCare, Boston, MA). The primary outcome was worsening HTN (BP≥160/100 mmHg on ≥1 occasion or requiring intensification of antiHTN therapy) in patients with pre-existing HTN, or the development of new HTN in patients with no prior history. Results: The most common cancers wererenal cell (32.2%), hepatocellular (11.6%), GIST (12.5%), and other sarcomas (15.3%). Most patients received sunitinib (52%), sorafenib (25.9%) or pazopanib (18%). Pre-existing HTN was present in 65.4%. The primary BP outcome was identified in 49.9% (median follow-up 4.3 months...

Clinicopathologic factors associated with the development of sunitinib induced hypertension (HTN) in patients (pts) with metastatic renal cell carcinoma (mRCC).

508 Background: The VEGFR inhibitor sunitinib is a standard treatment for metastatic renal cell carcinoma (mRCC). HTN, an on-target class effect of VEGF signaling-pathway inhibitors, has been shown to correlate with clinical outcome. Studies have shown the association between genetic polymorphisms in several genes, and the development of HTN in patients treated with targeted therapies. We aimed to study the association between readily available clinicopathologic factors and the development of sunitinib induced HTN in mRCC patients. Methods: Records from mRCC patients treated with sunitinib in 9 centers across 2 countries were retrospectively reviewed. Sunitinib induced HTN was defined as systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg. Analysis of the association between clinicopathologic factors and the development of HTN was performed using logistic regression. Results: Between 2004-2013, 302 patients with mRCC were treated with sunitinib. The incidence of sunitinib induced HTN was 50% (n=152). Clinicopathologic factors included in the analysis were age (median 63), gender (67% male), HENG risk (good 22%, intermediate 59%, poor 19%), smoking status (active 21%), BMI (obese=BMI ≥30, 28%; overweight=BMI 25-29.9, 37%; normal weight= BMI &lt;25, 35%), pre-treatment HTN (58%), past nephrectomy (83%), histology (73% clear cell), &gt; 1 metastatic site (82%), metastatic site (lung 72%, liver 25%, bones 40%), pre-treatment neutrophil to lymphocyte ratio (&gt;3 in 45%), treatment line (first vs advanced), sunitinib dose reduction/treatment interruption (45%). Absence of liver metastases (OR 3.5, p=0.02), pre-treatment neutrophil to lymphocyte ratio ≤ 3 (OR 5.5, p=0.001), and BMI (overweight and normal weight vs obese, OR 2.2 and 2.3 respectively, p=0.01 both) were independently associated with the development of HTN. Conclusions: In metastatic renal cell carcinoma patients treated with sunitinib, readily available clinicopathologic factors may be used to identify patients who are prone to the development of HTN.

Clinical development of VEGF signaling pathway inhibitors in childhood solid tumors.

Angiogenesis is a target shared by both adult epithelial cancers and the mesenchymal or embryonal tumors of childhood. Development of antiangiogenic agents for the pediatric population has been complicated by largely theoretical concern for toxicities specific to the growing child and prioritization among the many antiangiogenic agents being developed for adults. This review summarizes the mechanism of action and preclinical data relevant to childhood cancers and early-phase clinical trials in childhood solid tumors. Single-agent adverse event profiles in adults and children are reviewed with emphasis on cardiovascular, bone health, and endocrine side effects. In addition, pharmacological factors that may be relevant for prioritizing clinical trials of these agents in children are reviewed. Considerations for further clinical evaluation should include preclinical data, relative potency, efficacy in adults, and the current U.S. Food and Drug Administration approval status. Toxicity profiles of vascular endothelial growth factor (VEGF) signaling pathway inhibitors may be age dependent and ultimately, their utility in the treatment of childhood cancer will require combination with standard cytotoxic drugs or other molecularly targeted agents. In combination studies, toxicity profiles, potential drug interactions, and late effects must be considered. Studies to assess the long-term impact of VEGF signaling pathway inhibitors on cardiovascular, endocrine, and bone health in children with cancer are imperative if these agents are to be administered to growing children and adolescents with newly diagnosed cancers.

Effects of Novel Angiogenesis Inhibitors for the Treatment of Cancer on the Cardiovascular System

A 60 year-old man with a history of prostate cancer who underwent radical prostatectomy is currently being treated with androgen-deprivation therapy and is on a clinical trial with bevacizumab (Avastin, an antiangiogenic and anti–vascular endothelia growth factor [VEGF] chemotherapy) for an elevated prostate-specific antigen. At clinic visits after starting bevacizumab, he was noted to have new hypertension, with blood pressure as high as 178/98 mm Hg. After his second cycle of bevacizumab, he had sudden onset of palpitations, with workup revealing atrial fibrillation. He spontaneously cardioverted back to sinus rhythm but was referred to our institution's cardiology clinic for oncology patients (Cardio-Oncology Clinic) for management of hypertension and atrial fibrillation in the setting of bevacizumab therapy. Angiogenesis, the formation of new blood vessels from preexisting ones, is required for the growth and metastases of solid tumors.1 Angiogenesis is mediated by the stabilization of the master transcription factor (hypoxia-inducible factor-α), leading to transcription of a number of protumorigenic factors, including VEGF. Inhibiting this pathway has served as a target for antineoplastic treatment, and over the last 5 years, VEGF signaling pathway (VSP) inhibitors have been approved for the treatment of a broad spectrum of malignancies (the Figure). With increased clinical use, these agents have been shown to have cardiovascular side effects, most commonly hypertension, but also arterial or venous thrombotic events and heart failure. This review outlines the presentation, pathophysiology, and our approach to the diagnosis and treatment of VSP inhibitor–induced hypertension, and briefly highlights other cardiac complications that may occur in patients receiving these agents. Figure. Schematic of vascular endothelial growth factor (VEGF) pathway and sites of action of VEGF signaling pathway inhibitors (modified from templates provided by www.proteinlounge.com). VEGFR indicates VEGF receptor; HIF, hypoxia-inducible factor; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; and TKI, tyrosine kinase inhibitor. The VEGF …

Metronomic Oral Topotecan with Pazopanib Is an Active Antiangiogenic Regimen in Mouse Models of Aggressive Pediatric Solid Tumor

Low dose metronomic (LDM) chemotherapy, combined with VEGF signaling pathway inhibitors, is a highly effective strategy to coordinately inhibit angiogenesis and tumor growth in many adult preclinical cancer models. We have tested the efficacies of daily oral LDM topotecan alone and in combination with pazopanib, a VEGF receptor inhibitor, in three pediatric extracranial solid tumor mouse models. In vitro dose-response study of topotecan and pazopanib was conducted on several neuroblastoma, osteosarcoma, and rhabdomyosarcoma cell lines. In vivo antitumor efficacies of the LDM topotecan and pazopanib as single agents and in combination were tested on 4 subcutaneous xenograft models and on 2 neuroblastoma metastatic models. Circulating angiogenic factors such as circulating endothelial cells (CEC), circulating endothelial pro genitor cells (CEP), and microvessel densities were used as surrogate biomarker markers of antiangiogenic activity. In vitro, topotecan caused a dose-dependent decrease in viabilities of all cell lines, while pazopanib did not. In vivo, combination of topotecan + pazopanib (TP + PZ) showed significant antitumor activity and significant enhancement in survival compared with the respective single agents in all models. Reductions in viable CEP and/or CEC levels and tumor microvessel density were correlated with tumor response and therefore confirmed the antiangiogenic activity of the regimens. Pharmacokinetic studies of both drugs did not reveal any drug-drug interaction. Metronomic administration of TP + PZ showed a statistically significant antitumor activity compared with respective single agents in pediatric tumor mouse models and represent a valid option as a maintenance therapy in aggressive pediatric solid tumors.

Pharmacodynamic (PD) assessment of blood pressure (BP) in a randomized dose-ranging trial of sorafenib (S).

3016 Background: Hypertension may be a PD marker for efficacy of VEGF signaling pathway (VSP) inhibitors. The effects of S doses >800 mg/d on BP are not well characterized. To determine precisely the BP response to escalated doses of S, advanced solid tumor patients (pts; ECOG PS < 2 and screening BP < 140/90 mmHg on no antihypertensives) underwent serial 12-hour ambulatory BP measurement sessions (ABP) on different doses of S. Methods: The primary objective was to detect an increase in diastolic BP (DBP) proportional to the increased dose (based on prior data, assumed mean DBP increase for 400 mg BID = 6.0; on increased dose = 9.0 mmHg). ABP were conducted pre/post 7 d of S 400 mg BID. All pts then received no drug for 7 d, followed by another ABP. Pts with no > grade 2 toxicities during the first 2 wks were then randomized to receive escalated dose S at 400mg TID or 600mg BID. All pts repeated ABP after 7 d of additional S. Readings were collected every 10 min during daytime hrs (minimum # readings for evaluable session = 50). Results: 54 of a planned 58 pts were evaluable for data analysis by January 2011. Mean DBP elevation from baseline to Day 7 was 8.0 (SD= 6.5; 95% CI 6.3-9.8) mmHg. The variance in the change in DBP during the washout phase was unexpected, with 32/54 pts having DBP return to baseline (BL); 15/54 had DBP remain elevated and 7/54 had DBP decline below BL. After the 7 d washout, 18 were randomized to 400 mg TID, 19 to 600 mg BID, and 17 received 400 mg BID again. To detect the dose escalation effects on ABP, Day 22 DBP was fit to a regression model with main effect terms for Day 7 DBP and Day 14 DBP and interaction terms for BL DBP, age, sex, race (AA vs. other), and BSA. The final model (R2= 0.73; p < 0.00001) included terms for BL, Day 7, and Day 14 DBP. Compared to 400 mg BID, mean DBP with 400 mg TID was 4.7 mmHg greater (p=0.15, 95% CI -1.7, 11). Mean DBP for the 600 mg BID arm was 2.6 mmHg greater (p=0.41, 95% CI -3.7, 8.8). The difference between the 2 dose escalation arms was not significant (p=0.25). Conclusions: Escalating S dose in a pt population did not uniformly lead to further DBP elevations. To enhance efficacy of S, and perhaps other VSP inhibitors, will likely require a more complex PD-based scheme than dose-to-hypertension.

Sorafenib-associated multivessel coronary artery vasospasm

Cardiotoxicity associated with cancer treatment is an important field of interest especially as the new class of VEGF signaling pathway inhibitors (VSP) continues to grow. Small molecule tyrosine kinase inhibitors such as sorafenib, sunitinib, and pazopanib inhibit the downstream pathways of all three of the vascular endothelial growth factor receptors (VEGFR 1, 2, and 3). Other targets of these agents include kinases involved in vascular and myocardial homoeostasis. These agents are all known to frequently cause hypertension, their most common side-effect. Myocardial ischemia has also been reported, but the frequency and etiology of VSP-related ischemia is poorly characterized. This manuscript describes the first reported case of sorafenib-associated multivessel coronary vasospasm in a 57-year-old patient with hepatocellular carcinoma. He underwent sorafenib treatment, a tyrosinase inhibitor, 400 mg twice a day. The vasospasm was reversible under nitroglycerin. Possible mechanisms are also discussed.

Hypertension (HTN) as a potential biomarker of efficacy in patients (pts) with gastrointestinal stromal tumor (GIST) treated with sunitinib (SU).

38 Background: HTN is a class effect of VEGF signaling pathway inhibitors. SU is a multitargeted inhibitor of VEGFRs and other receptor tyrosine kinases. Associations between SU-induced HTN and efficacy endpoints (OS, PFS, TTP, and ORR) in pts with imatinib-resistant/intolerant GIST from 2 prospective clinical trials were investigated retrospectively. Methods: This analysis included pooled data from 319 pts who received SU and had post-baseline blood pressure (BP) data available. Tumor response data were based on investigator assessments. Most pts (87%) received SU 50 mg/d on the standard 4-wk-on/2-wk-off schedule. BP was measured on the first and last day of dosing in each treatment cycle at a minimum. HTN was defined as max or mean SBP ≥ 140 or DBP ≥ 90 mmHg. OS, PFS, and TTP were estimated by Kaplan—Meier methods and compared between pts with vs. without HTN using the log-rank test. The influence of prognostic risk factors was analyzed using a Cox proportional hazards model. Results: 233 and 187 pts (73% and 59%) had ≥ 1 HTN episode as defined by max SBP and DBP, respectively. Efficacy results significantly favored pts who developed HTN on SU based on max SBP or DBP (eg, median OS for pts with HTN [max SBP] was 89.4 weeks vs. 53.1 weeks for pts without HTN [p = 0.0001]). Using HTN onset as a time-dependent covariate, HTN defined by max DBP was a significant predictor of prolonged TTP and PFS, and HTN defined by both max SBP and DBP was a significant predictor of prolonged OS (p &lt; 0.05). In multivariate analysis, HTN defined by max SBP or DBP was a significant independent predictor of improved OS, PFS, and TTP (p &lt; 0.0001). Analysis of any-grade and grade ≥3 cerebrovascular, ocular, cardiac, and renal AEs in pts with/without HTN is ongoing and will be presented. Clinical outcomes were not compromised in pts treated with anti-HTN medications. Conclusions: SU-associated HTN was significantly and independently associated with improved clinical outcomes, supporting the hypothesis that HTN is a biomarker for antitumor efficacy in pts with GIST treated with SU. Serial BP monitoring and standard use of anti-HTN medications, which were not shown to compromise efficacy, are recommended during SU therapy. [Table: see text]

Pazopanib for the Treatment of Patients with Advanced Renal Cell Carcinoma

Dramatic advances in the care of patients with advanced renal cell carcinoma have occurred over the last ten years, including insights into the molecular pathogenesis of this disease, that have now been translated into paradigm-changing therapeutic strategies. Elucidating the importance of signaling cascades related to angiogenesis is notable among these achievements. Pazopanib is a novel small molecule tyrosine kinase inhibitor that targets VEGFR-1, -2, and -3; PDGFR-α, PDGFR-β; and c-kit tyrosine kinases. This agent exhibits a distinct pharmacokinetic profile as well as toxicity profile compared to other agents in the class of VEGF signaling pathway inhibitors. This review will discuss the scientific rationale for the development of pazopanib, as well as preclinical and clinical trials that led to approval of pazopanib for patients with advanced renal cell carcinoma. The most recent information, including data from 2010 national meeting of the American Society of Clinical Oncology, and the design of ongoing Phase III trials, will be discussed. Finally, an algorithm utilizing Level I evidence for the treatment of patients with this disease will be proposed.